Historically, development of successful treatments for various psychiatric conditions has been based on an understanding of the mechanisms mediating the condition. Similar principles have been applied to the treatment of substance use disorders including alcohol drinking;a prime example is the elegant preclinicalclinical developmental profile of the use of naltrexone for reducing alcohol drinking. Evidence from our ongoing project in CTNA1 significantly adds to this literature and suggests that the efficacy of naltrexone is moderated by the presence of a family history of alcoholism. The current proposal is based on initial evidence from our group suggesting that alcohol craving is altered by the glutamatergic agent memantine. This follows preclinical evidence in the literature and clinical evidence from other members of our group indicating that glutamatergic antagonists have alcohol-like effects and that the presence of a family history of alcoholism alters the dysphoric effects of these agents. Therefore, we are now proposing to evaluate the efficacy of memantine in reducing alcohol drinking in a laboratory model of alcohol self-administration. This model has been developed and validated using naltrexone (O'Malley et al., 2002) and is currently used by our and other groups to screen medications. In the current proposal we will evaluate the effects of memantine on alcohol drinking behavior, alcohol craving and stimulation/sedation in non-treatment seeking, alcohol-dependent heavy drinkers with either a positive or negative family history of alcoholism. We will test the following specific aims: Specific Aim 1: To evaluate the efficacy of seven days of pretreatment with one of three doses of memantine (placebo, 20 mg and 40 mg/day) using a laboratory model consisting of exposure to a priming drink of alcohol and subsequent freechoice drinking during a three-hour drinking period. Specific Aim 2: To evaluate the influence of family history of alcoholism on the efficacy of memantine. Exploratory aims will also evaluate the presence of a polymorphism of the spinophillin gene as well impulsivity and delayed discounting measures as correlates of alcohol responses, drinking behavior and memantine efficacy. Thus, the results of this proposal will provide an initial signal regarding the potential clinical utility of memantine to reduce alcohol drinking in alcohol dependent individuals.